Why does Huntington's Disease (HD) affect the brain while Huntington protein (Htt) is expressed in every tissue of the body? Secondly, does the CAG trinucleotide expansion mutation in HD gene (HTT) occurs only in the brain?
HTT is ubiquitously expressed and over the past decade it has become apparent that patients with HD experience a wide array of peripheral organ dysfunction including, weight loss, HD-related cardiomyopathy, skeletal muscle wasting and severe metabolic phenotype. (e.g. Front Physiol. 2014 Oct 6;5:380. doi: 10.3389/fphys.2014.00380. eCollection 2014; Lancet Neurol. 2009 Aug;8(8):765-74. doi: 10.1016/S1474-4422(09)70178-4; Neurology. 2008 Nov 4;71(19):1506-13. doi: 10.1212/01.wnl.0000334276.09729.0e. and others)
Also see http://www.ncbi.nlm.nih.gov/pubmed/10196370 . Huntington results in multisystem failure but the nervous system is the first to break down. The basal ganglia show glial pathology before there is any neuronal pathology (I forget the actual reference but here is a place to start reading http://www.ncbi.nlm.nih.gov/pubmed/24938402 ).
@T. Genade: "The basal ganglia show glial pathology before there is any neuronal pathology". There is no research backing up this statement in HD patients. That glial cells are affected and actually decrease in number in HD patients was published in 1975 and 1976.
Thanks Herwig, do you have the references for those articles? I'm not sure if we understand each other. You seem to imply that the glia degenerate first which is what I also implied? I know there are mouse papers that show this... are those the 1975/6 papers or do those paper show evidence for human glial degeneration? It is hard tracking down the glial papers as neurons are the focus of so much of the research. Thanks
@ Tyrone: here are the ancient papers:
Schröder, K.F., Hopf, A., Lange, H.W., Thörner, G.
Morphometrisch-statistische Strukturanalyse des Striatum, Pallidum und Nucleus subthalamicus beim Menschen. I. Striatum.
Journal für Hirnforschung 16 (4): 333-350 (1975)
Thörner, G., Lange, H.W., Hopf, A.
Morphometrisch-statistische Strukturanalyse des Striatum, Pallidum und Nucleus subthalamicus beim Menschen. II. Pallidum.
Journal für Hirnforschung 16 (5): 401-413 (1975)
Lange, H.W., Thörner G., Hopf, A.
Morphometrisch-statistische Strukturanalyse des Striatum, Pallidum und Nucleus subthalamicus beim Menschen. III. Nucleus Subthalamicus.
Journal für Hirnforschung 17 (1): 31-41 (1976)
Lange, H.W., Thörner, G., Hopf, A., Schröder, K.F.
Morphometric studies of the neuropathological changes in choreatic diseases.
J Neurol Sci 1976 Aug;28(4):401-425
In all investigated nuclei the total number of glial cells was reduced. But i doubt that glial changes ocur before neuronal changes, which are much more prominent than the glial changes.
Based on upcoming literature, and to my understanding, it is evident that a faulty metabolism can augment the neurodegenerative processes. At the same time, it does not mean that glial cells degenerate before neurodegeneration, rather a faulty metabolic supply probably owing to reduced lactate shuttle by astrocytes to neurons seems to exacerbate neurodegeneration which is already in place. However, once neurons start to degenerate, this may then result in activation of glial cells, such as activation of microglia, which further fuels the degenerative process, thus making it a vicious cycle.
Therapeutic studies targeting microglia activation show that there is slowed degeneration, but not complete ablation of neuronal death. Thus, being a support system to the CNS, glial cells have an impact on the health of the CNS, but can't be blamed for everything.
The aspect of lactate metabolism is interesting. The normal brain takes up more glucose than actually needed for energy production, and gives lactate into the venous blood. Not so in HD: the HD brain takes up lactate - maybe as an attempt to compensate a deficient energy production in the mitochondria. (We reported this finding in 1985 - largely unnoticed.)
It does not only affects the brain but also other organs. The genetic abnormality is universal and it was found to affect heart and many organs. However, the most evident clinical symptoms is the neurological symptoms.
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